9 May 2008
Alexander van Oudenaarden
The propagation of information through signaling cascades spans a wide range of time-scales, including the rapid ligand-receptor interaction and the much slower response of downstream gene expression. To determine which dynamic range dominates a response, we used periodic stimuli to measure the frequency dependence of signal transduction in the osmo-adaptation pathway of Saccharomyces cerevisiae. We applied system identification methods to infer a concise predictive model . We found that the dynamics of the osmo-adaptation response are dominated by a fast-acting negative feedback through the kinase Hog1.
Negative feedback can serve many different cellular functions, including the reduction of noise in transcriptional networks and the creation of oscillations in circadian systems. However, only one special type of negative feedback ("integral feedback") can ensure robust performance in homeostatic systems, yielding a system behavior termed perfect adaptation, where steady-state output is independent of steady-state input. We measured single-cell dynamics in the Saccharomyces cerevisiae hyperosmotic shock network, which regulates membrane turgor pressure. Importantly, we found that the nuclear enrichment of the MAP kinase Hog1 perfectly adapts. We used small-molecule inhibitors and dynamic measurements of cell volume, Hog1 nuclear enrichment, and glycerol accumulation to assess the network location of the mechanism responsible for perfect adaptation, and we built a concise model of the system. Notably, Hog1 kinase activity, but not gene expression, is required for Hog1 perfect adaptation, suggesting that this network's homeostatic function may critically depend on protein-protein interactions.
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